The extent of brain damage caused by stroke largely depends on how quickly blood flow is restored, and the patient's immune response also plays an important role. Researchers at the Stroke and Dementia Research Institute of the Ludwig Maximilian University Hospital Munich (LMU), led by Dr. Corinne Benakis, have identified a bacteria-derived signal that shapes this immune response and affects stroke outcome. According to Medical Xpress, this research was published in the journal Cell.
The researchers found that in mice with severe stroke, the abundance of gut bacteria that produce indole increases; a metabolite made only in the gut. These bacteria carry the tnaA gene, which enables them to convert the dietary amino acid tryptophan into indole. In mice, these bacteria exacerbated brain damage after stroke.
Indole acts on a receptor called AHR (aryl hydrocarbon receptor) that is present in dendritic cells. These immune cells monitor the intestinal lining and help coordinate immune responses. When the researchers specifically inactivated AHR in these cells, the mice were better protected against brain damage.
Dr. Rosa Delgado Jiménez, one of the first authors of the paper, explains that dendritic cells have long, branch-like protrusions that sense environmental changes, including metabolites from gut bacteria. With AHR inactivated, the behavior of these cells changed markedly and they were able to migrate more easily from the gut to the meninges, the membranes surrounding the brain. They also boosted protective T cells and helped reduce brain damage.
There is also evidence that this pathway may play a role in humans. In a group of patients with ischemic stroke, a higher abundance of the bacterial tnaA gene was associated with worse functional outcomes after stroke. Bacteria carrying this gene were also more abundant in individuals with stroke risk factors, including obesity and type 2 diabetes.
The study made use of facilities at the Interregional Research Center on Regulatory T Cells. Benakis says the work required expertise their small group did not have alone, and they collaborated with the European Molecular Biology Laboratory and the Technical University of Munich to identify microbial tryptophan metabolites and indole, which is technically challenging.
These findings raise an important question for future research: in healthy individuals, can changes in the gut microbiome or its metabolites prime the immune system to respond differently if a stroke occurs? Delgado Jiménez emphasizes that stroke is usually considered a localized injury to the brain, but the findings indicate the gut can also help shape the immune response. Benakis adds that it must first be determined whether the mechanism found in mice also occurs in humans; however, these results open the way to investigate whether targeting the gut microbiota, including preventive approaches in high-risk individuals, can improve stroke outcomes.